ipso-Cyclization Strategy for

Jun 16, 2017 - A variety of MBH-carbonates having aryl or heteroaryl groups on the alkyne functionality fruitfully participated in the one-pot ipso-an...
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One-Pot Consecutive Sulfonamidation/ipso-Cyclization Strategy for the Construction of Azaspirocyclohexadienones Chada Raji Reddy,*,†,‡ Ravi Ranjan,†,‡ Santosh Kumar Prajapti,† and Kamalkishor Warudikar†,‡ †

Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India Academy of Scientific and Innovative Research, New Delhi 600113, India

‡

S Supporting Information *

ABSTRACT: Harnessing of Morita−Baylis−Hillman (MBH) carbonates of acetylenic aldehydes as handy synthons has allowed a facile synthesis of azaspirocyclohexadienones by sequential DABCO-promoted sulfonamidation/ICl-mediated ipsoiodocyclization reactions. A variety of MBH-carbonates having aryl or heteroaryl groups on the alkyne functionality fruitfully participated in the one-pot ipso-annulation reaction to provide the corresponding 3-iodo spirocyclohexadienones. The sulphonamide functionality was further utilized to construct the tricyclic fused-sultam framework.

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INTRODUCTION During the past decade, synthesis of functionalized spirocylcohexadienones through ipso-cyclization has received considerable attention1 due to their remarkable biological activities (Figure 1) and potential utility for forming charge-transfer complexes.2

Scheme 1. ipso-Cyclization to Azaspirocyclohexadienones

Figure 1. Prevalence of spirocyclohexadienone in bioactive natural products.

substrates (Scheme 1b)5 toward the synthesis of azaspirocylcohexadienones. All these effective methods require preconstruction of the desired alkynyl amide or amine. Considering the importance of azaspirocylcohexadienones, the development of new strategies is required for their one-pot synthesis. Our research group has investigated the one-pot reactions using 1-aryl propargylic alcohols6 and Morita−Baylis−Hillman

In addition, these cyclohexadienones serve as key intermediates to access polycyclic molecular frameworks as well as natural products via synthetic manipulations.3 Indeed, several ipsoannulation approaches to spirocylcohexadienones have been developed. Majority of them involves the halogen or their derivative induced electrophilic cyclization of N-arylpropiolamide precursors (Scheme 1a),4 besides few nonamide © 2017 American Chemical Society

Received: May 24, 2017 Published: June 16, 2017 6932

DOI: 10.1021/acs.joc.7b01285 J. Org. Chem. 2017, 82, 6932−6939

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

a

entry

(sulfonamidation) catalyst (5 mol%), solvent, temp, time

1 2 3b 4 5 6 7 8 9 10c

DABCO, CH3CN, 0 °C, 30 min DABCO, CH2CI2, 0 °C, 30 min CH2CI2, 0 °C 30 min

(ipso-cyclization) reagent (1 equiv), solvent, temp, time

product

yield (%) 45 81

I2/NaHC03, toluene, −78 °C, 6 h I2/NaHC03, CH2CI2, −78 °C, 6 h I2/NaHC03, CH2CI2, 0 °C, 6 h ICI, toluene, −78 °C, 1 h ICI, CH2CI2, −78 °C, 1 h ICI, CH2CI2, 0 °C, 30 min ICI, CH2CI2, 0 °C, 30 min

l-3a l-3a l-3a 3a 3a 3a 3a 3a 3a 3a

DABCO, CH2CI2, 0 °C, 30 min

23 31 30 58 68 84 81

MBH-carbonate (1 equiv) and N-(4-methoxyphenyl)-tolylsulfonamide (1.1 equiv). bln absence of catalyst, no reaction occurred. cOne-pot reaction.

adducts of acetylenic aldehydes7 toward the synthesis of various heterocycles, carbocycles, aromatic and polyaromatic hydrocarbons. The use of these substrates has been proven to be highly convenient for the formation of desired intermediate followed by its annulation in a single reaction vessel, which minimizes the solvent usage and chemical waste generated. Encouraged by the realization that MBH-adduct of acetylenic aldehyde has the potential to construct the spirocyclohexadienones if identified suitable reaction conditions, we envisaged a new one-pot approach to azaspirocyclohexadienones through sequential sulfonamidation/ipso-cyclization reaction strategy (Scheme 1c).

(entry 2). No reaction was observed when omitting DABCO from the reaction (entry 3), thus verifying the need of DABCO. Next, the ipso-cyclization was studied using different iodinebased reagent systems. The treatment of I-3a with I2/NaHCO3, independently in toluene and CH2Cl2, at −78 °C provided the azaspirocylcohexadienone 3a in 23% and 31% yields, respectively (entries 4 and 5). The increase in reaction temperature did not help to improve the yields (entry 6). When, the ipso-cyclization was carried out in the presence of ICl in toluene at −78 °C, the reaction proceeded well to give 3a in 58% yield (entry 7). The yield of 3a improved to 68% in the presence of CH2Cl2 (entry 8). To our delight, azaspirocylcohexadienone 3a was found in 84% yield, under ICl in CH2Cl2 at 0 °C for 30 min (entry 9) and lower yield (62%) observed at room temperature. At this point of the examination, we speculated the ipso-cyclization can be carried out in situ after generation of intermediate I-3a. In addition, it was observed that the isolation of N-propargylated sulfonamide I-3a in high yield was found to be difficult. These findings encouraged us to explore the feasibility of a sequential one-pot synthesis by combining MBH-carbonate 1a, N-(4-methoxyphenyl)-tolylsulfonamide 2a, DABCO, and then ICl at 0 °C. Indeed, this onepot reaction progressed smoothly to give 3a in 81% yield (Table 1, entry 10). With suitable reaction conditions in hand, we investigated a range of diversely substituted MBH-carbonates with N-(4methoxyphenyl)-tolylsulfonamide 2a (Scheme 2). It was found that, the MBH-carbonate 1b having naphthalyl substitution on alkyne functionality reacted well to give azaspirocylcohexadienone 3b in 82% yield. MBH-carbonates with electron-donating and deficient groups on the phenyl group attached to alkyne were reacted well demonstrating little influence on the ipsocyclization in terms of reaction time and product yield. The MBH-carbonate bearing aryl substitution with electrondonating groups (4-OMe, 4-Me) took less reaction time for complete conversion to give 3c (92%) and 3d (88%). Similarly, 3,5-dimethyl phenyl MBH-carbonate 1e was also consistent

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RESULTS AND DISCUSSION This new strategy was planned in such a way that, the N-aryl propargylamine (precursor for ipso-cyclization) would be generated through the sulfonamidation reaction of MBHcarbonate 1 of acetylenic aldehyde with N-arylsulfonamide 2 and subjected to electrophilic ipso-halocyclization in one-pot to obtain the corresponding azaspirocylcohexadienones 3. To the best of our knowledge, there are no earlier reports for the sulfonamidation of MBH-carbonate 1 with N-arylsulfonamide 2, while very limited methods available with primary sulphonamides or N-alkylsulfonamides.8 Furthermore, examples of the ipso-cyclization of N-aryl propargylsulfonamides are rare.5b Herein, we report the first example of one-pot sulfonamidation/ipso-cyclization strategy to azaspirocyclohexadienones. As a starting point, we investigated the reaction of MBHcarbonate 1a and N-(4-methoxyphenyl)-tolylsulfonamide 2a to find the suitable reaction condition for sulfonamidation (Table 1). Initial experimentation indicated that the desired N-(4MeO-phenyl)-N-propargylated tolylsulfonamide I-3a formed in 45% yield in acetonitrile solvent at 0 °C in the presence of DABCO (5 mol%) (Table 1, entry 1). Altering the solvent to dichloromethane was found to increase yield of I-3a to 81% 6933

DOI: 10.1021/acs.joc.7b01285 J. Org. Chem. 2017, 82, 6932−6939

Article

The Journal of Organic Chemistry Scheme 2. Scope of MBH-Carbonatesa

Scheme 3. Scope of Sulfonamidesa

a

Reaction conditions: 1a or 1d (1 equiv), N-(4-methoxphenyl)sulfonamide (1.1 equiv), DABCO (5 mol%), CH2CI2 (5 mL), 0 °C then ICI (1 equiv), 0 °C. bCarbonate 1d used as substrate.

Based on the above results and literature knowledge, a possible reaction pathway for this consecutive sulfonamidation/ ipso-cyclization is proposed (Scheme 4). Initially, DABCO facilitates the C−N bond formation between 1a and 2a to give I-3a via intermediates A and B along with its regeneration.9 Next, the addition of ICl to I-3a allows the formation of iodonium intermediate C, which undergoes ipso-cyclization to

a Reaction conditions: MBH-carbonate (1 equiv), N-(4-methoxphenyl)-tolylsulfonamide (1.1 equiv) DABCO (5 mol%), CH2CI2 (5 mL), 0 °C then ICI (1 equiv) 0 °C. bIntermediate I-3I was isolated

Scheme 4. Proposed Reaction Mechanism

with optimal reaction conditions and gave 3e in 93% yield. Substrates 1f−1h with electron withdrawing groups (4-Cl, 4COCH3, 4-CN) on phenyl ring required longer reaction times and delivered corresponding products 3f−h in 65 to 70% yield. 3-Trifluoromethylphenyl group also well tolerated in the reaction of 1i to give 3i in 70% yield. MBH-carbonates generated from heteroaryl acetylenic aldehydes 1j and 1k, could also be used to prepare the corresponding 3-iodo azaspiro[4,5]trienones 3j and 3k in good yields, although 1k took prolonged reaction time. The reaction of MBH-carbonate tethered with aliphatic group (1l) failed to give the ipso-cyclized product, instead intermediate I-3l was obtained in 64% yield. We next set out to explore the scope of N-substituted sulfonamides using 1a as the reaction partner under optimized reaction conditions (Scheme 3). Fascinatingly, the substrate containing N-alkyl sulfonamides 2b (Me), 2c (Et), 2d (cyclopropyl) underwent sequential sulfonamidation/ipso-cyclization reactions to give spirotrienones 3m, 3n, and 3o, respectively, in good yields. Similarly, N-benzyl sulfonamide 2e could successfully be employed in the reaction to obtain 3p in 76% yield. Furthermore, the present method was extended to 2bromo-N-(4-methoxyphenyl)benzenesulfonamide 2f with MBH-carbonate 1d to furnish the product 3q in 84% yield. 6934

DOI: 10.1021/acs.joc.7b01285 J. Org. Chem. 2017, 82, 6932−6939

Article

The Journal of Organic Chemistry

Usefulness of the spirocyclohexadienones has also been demonstrated to access tricyclic-fused sultam and other diversified derivatives.

form the desired spirocyclic compound 3a through spirocyclic intermediate D.5b Subsequently, we turned our attention to explore the utility of obtained spirotrienone for the synthesis of sultam (cyclic sulfonamides), privileged scaffold in drug discovery due to its diverse biological activities.11 In this direction, the spirocyclohexadienone 3m, bearing N-mesyl group, was subjected to stereoselective Michael addition10 in the presence of LiHMDS to obtain tricyclic-fused sultam derivative 4 in 75% yield (Scheme 5). The stereochemistry of the product was determined by X-ray crystallographic analysis (see the Supporting Information, Figure S1).

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EXPERIMENTAL PROCEDURES AND ANALYTICAL DATA

General Information. Reactions were monitored by thin-layer chromatography carried out on silica plates using UV-light and anisaldehyde or β-naphthol for visualization. Column chromatography was performed on silica gel (60−120 mesh) using n-hexane and ethyl acetate as eluent. Evaporation of solvents was conducted under reduced pressure at temperatures less than 40 °C. FTIR spectra were recorded on KBr thin film. 1H NMR (300, 400, and 500 MHz) and 13 C NMR (75, 101, and 126 MHz) spectra were recorded in CDCl3 solvent. Chemical shifts δ and coupling constants J are given in ppm (parts per million) and Hz (hertz), respectively. Chemical shifts are reported relative to residual solvent as an internal standard for 1H and 13 C (CDCl3: δ 7.26 ppm for 1H and 77.0 ppm for 13C). Mass spectra were obtained on VG 70-70H or LC/MSD trap SL spectrometer operating at 70 eV using direct inlet system. High-resolution mass spectra (HRMS) [ESI+] were obtained using either a TOF or a double-focusing spectrometer. General Procedure for the Preparation of MBH-Carbonates, 1a−1k. To a stirred solution of the corresponding MBH-alcohol (1 mmol) in 10 mL of CH2Cl2 was added di-tert-butyl dicarbonate (0.262 g, 1.2 mmol) and DMAP (6.1 mg, 0.05 mmol) at 0 °C and stirred for given time. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (EtOAc: n-hexanes) to afford the corresponding MBH-carbonates. All these carbonates were fully characterized and spectral data for new compounds are given below. Methyl 3-((tert-Butoxycarbonyl)oxy)-2-methylene-5-(naphthalen-1-yl)pent-4-ynoate (1b). 1.15 g, 84% yield, yellow liquid, Rf = 0.8 (n-hexane:EtOAc = 9:1); 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.4 Hz, 1H), 7.85−7.81 (m, 2H), 7.69 (dd, J = 7.1, 1.0 Hz, 1H), 7.57−7.48 (m, 2H), 7.41 (dd, J = 8.2, 7.2 Hz, 1H), 6.58−6.56 (m, 1H), 6.52 (s, 1H), 6.45−6.43 (m, 1H), 3.86−3.81 (m, 3H), 1.54 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 165.0, 152.3, 136.5, 133.4, 133.1, 130.9, 129.5, 129.4, 128.3, 127.0, 126.5, 126.0, 125.1, 119.5, 88.4, 85.8, 83.2, 65.2, 52.3, 27.8; IR (KBr): νmax = 2984, 1736, 1254, 1151, 1069,953, 850, 781 cm−1; MS (ESI): m/z 389 (M+Na)+; HRMS (ESI): m/z calcd for C22H23O5 (M+H)+: 367.1540; found 367.1540. Methyl 3-((tert-Butoxycarbonyl)oxy)-2-methylene-5-(p-tolyl)pent-4-ynoate (1d). 1.29 g, 90% yield, white solid, Rf = 0.7 (nhexane:EtOAc = 9:1); 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.51 (s, 1H), 6.36 (d, J = 9.6 Hz, 2H), 3.81 (s, 3H), 2.35 (s, 3H), 1.52 (d, J = 5.1 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 164.9, 152.2, 139.1, 136.5, 131.8, 129.4, 129.1, 129.0, 129.0, 118.8, 87.9, 83.1, 82.8, 64.9, 52.2, 27.7, 21.5; IR (KBr): νmax = 2983, 2232, 1737, 1252, 1150, 1077,951, 813 cm−1; MS (ESI): m/z 353 (M+Na)+; HRMS (ESI): m/z calcd for C19H22O5Na (M +Na)+: 353.1359, found: 353.1376. Methyl 3-((tert-Butoxycarbonyl)oxy)-5-(3,5-dimethylphenyl)-2methylenepent-4-ynoate (1e). 1.24 g, 88% yield, yellow liquid, Rf = 0.8 (n-hexane:EtOAc = 9:1); 1H NMR (500 MHz, CDCl3) δ 7.09 (s, 2H), 6.97 (s, 1H), 6.51 (s, 1H), 6.36 (d, J = 6.8 Hz, 2H), 3.81 (s, 3H), 2.28 (s, 6H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 164.9, 152.2, 137.8, 136.5, 130.8, 129.6, 129.3, 121.5, 88.1, 83.0, 82.8, 64.9, 52.2, 27.7, 21.0; IR (KBr): νmax = 2981, 2229, 1737, 1255, 1151, 1075,953, 847 cm−1; MS (ESI): m/z 367 (M+Na)+; HRMS (ESI): m/ z calcd for C20H24O5Na (M+Na)+: 367.1516, found: 367.1534. Methyl 5-(4-Acetylphenyl)-3-((tert-butoxycarbonyl)oxy)-2-methylenepent-4-ynoate (1g). 0.99 g, 72% yield, yellow liquid, Rf = 0.4 (n-hexane:EtOAc = 9:1); 1H NMR (500 MHz, CDCl3) δ 7.82−7.79 (m, 2H), 7.46−7.42 (m, 2H), 6.43 (s, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 3.72 (s, 3H), 2.49 (s, 3H), 1.42 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 197.0, 164.6, 152.0, 136.7, 136.1, 131.9, 129.2, 128.1, 126.5, 86.7,

Scheme 5. Synthesis of Tricyclic-fused Sultam 4

Finally, further diversification of the iodo-spirocyclohexadienone was also studied through Palladium-catalyzed coupling reactions (Scheme 6). In the first case, Suzuki coupling12a of Scheme 6. Diversified Analogues of 3c and 3m

3m with 4-hydroxyphenyl boronic acid gave the coupled product 5 in 68% yield. Likewise, 3m was subjected to Heck reaction12b with methyl acrylate to afford 6 in 74% yield. In addition, the Sonogashira reaction12c of 3c with phenylacetylene in the presence of PdCl2(PPh3)2/CuI provided 7 in 88% yield.

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CONCLUSION In conclusion, we have described the first one-pot protocol for the synthesis of azaspirocyclohexadienones via sequential sulfonamidation/ipso-cyclization reactions using MBH carbonate and N-aryl sulfonamide. This tandem reaction represents a simple and efficient approach to azaspirocyclohexadienones involving sequential C−N, C−I, and C−C bond formations. 6935

DOI: 10.1021/acs.joc.7b01285 J. Org. Chem. 2017, 82, 6932−6939

Article

The Journal of Organic Chemistry 86.5, 83.2, 64.6, 52.2, 27.6, 26.5; IR (KBr): νmax = 2985, 1737, 1685, 1361,1250, 1149, 1078, 953, 843, 751 cm−1; MS (ESI): m/z 381 (M +Na)+; HRMS (ESI): m/z calcd for C20H22O6Na (M+Na)+: 381.1309, found: 381.1324. Methyl 3-((tert-Butoxycarbonyl)oxy)-5-(4-cyanophenyl)-2-methylenepent-4-ynoate (1h). 0.99 g, 70% yield, yellow liquid, Rf = 0.8 (n-hexane:EtOAc = 9:1); 1H NMR (300 MHz, CDCl3) δ 7.50 (dd, J = 23.0, 8.3 Hz, 4H), 6.45 (s, 1H), 6.26 (d, J = 21.9 Hz, 2H), 3.74 (s, 3H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 164.5, 152.0, 136.0, 132.4, 132.0, 129.2, 126.6, 118.1, 112.3, 87.9, 85.6, 83.4, 64.5, 52.3, 27.6; IR (KBr): νmax = 2984, 2230, 1737, 1252, 1150, 1078, 954, 844, 752 cm−1; MS (ESI): m/z 364 (M+Na)+; HRMS (ESI): m/z calcd for C19H19NO5Na (M+Na)+: 364.1155, found: 364.1185. Methyl 3-((tert-Butoxycarbonyl)oxy)-2-methylene-5-(3(trifluoromethyl)phenyl)pent-4-ynoate (1i). 0.94 g, 70% yield, yellow liquid, Rf = 0.8 (n-hexane:EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.54 (dd, J = 14.6, 7.8 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 6.46 (s, 1H), 6.30 (d, J = 0.8 Hz, 1H), 6.26 (s, 1H), 3.75 (s, 3H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 164.7, 152.1, 136.2, 135.0, 129.3, 128.8, 128.7, 125.5, 122.8, 85.9, 85.2, 83.4, 64.6, 52.3, 27.7; IR (KBr): νmax = 2925,1737,1256, 1132, 1079, 956, 801, 694 cm−1; MS (ESI): m/z 407 (M+Na)+; HRMS (ESI): m/z calcd for C19H19F3O5Na (M+Na)+: 407.1077, found: 407.1099. General Procedure for the Preparation of 3a−3k. To a solution of MBH carbonate 1a to 1k (1 mmol) and N-(4methoxyphenyl)-4-methylbenzenesulfonamide 2a (1.1 mmol) in 5 mL of CH2Cl2 was added DABCO (5 mol%) at 0 °C and stirred up to 30 min. Then, ICl (1 mmol) was added dropwise to the reaction mixture at 0 °C. After the completion of reaction (monitored by TLC), saturated aqueous Na2S2O3·5H2O solution (10 mL) was added to the reaction mixture and extracted with CH2Cl2 (2 × 10 mL), washed with brine (2 × 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (EtOAc:hexanes) to afford the corresponding spirocyclohexadienones 3a to 3k. Methyl 3-((N-(4-Methoxyphenyl)-4-methylphenyl)sulfonamido)2-methylene-5-phenylpent-4-ynoate (I-3a). 234 mg, 81% yield, yellow solid, mp: 119−120 °C, Rf = 0.6 (n-hexane:EtOAc = 9:1); 1 H NMR (400 MHz, CDCl3) δ 7.68−7.62 (m, 2H), 7.36−7.28 (m, 3H), 7.27−7.21 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.02−6.97 (m, 2H), 6.76−6.71 (m, 2H), 6.58 (s, 1H), 6.21 (s, 1H), 5.78 (d, J = 1.9 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 2.36 (s, 3H);13C NMR (101 MHz, CDCl3) δ 165.4, 159.6, 143.2, 136.6, 136.4, 131.4, 129.0, 128.7, 128.4, 128.3, 122.0, 113.8, 88.4, 84.6, 55.3, 52.4, 52.1, 21.5; IR (KBr): νmax = 2952, 1726, 1505, 1348, 1247, 1159, 1029, 752, 665 cm-1; MS (ESI): m/z 498 (M+Na)+; HRMS (ESI): m/z calcd for C27H26NO5S (M+H)+: 476.1526, found: 476.1534. Methyl 2-(3-Iodo-8-oxo-4-phenyl-1-tosyl-1-azaspiro[4.5]deca3,6,9-trien-2-yl)acrylate (3a). 300 mg, 81% yield, white solid, mp: 206−208 °C, Rf = 0.3 (n-hexane:EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.36−7.29 (m, 4H), 7.27 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 10.1, 2.8 Hz, 1H), 7.07−6.98 (m, 2H), 6.86 (dd, J = 9.9, 2.6 Hz, 1H), 6.56 (s, 1H), 6.20 (dd, J = 10.0, 1.9 Hz, 1H), 6.13 (dd, J = 10.8, 2.6 Hz, 2H), 5.56 (s, 1H), 3.68 (s, 3H), 2.46 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.5, 164.4, 147.6, 147.5, 144.0, 144.0, 136.9, 132.9, 132.6, 129.8, 129.4, 129.4, 129.1, 128.2, 128.1, 97.7, 74.5, 51.8, 21.6; IR (KBr): 3020, 2925, 2854, 1667, 1350, 1160, 1073, 764, 664 cm−1; MS (ESI): m/z 610 (M+Na)+; HRMS (ESI): m/z calcd for C26H22INO5SNa (M+Na)+: 610.0156, found: 610.0189. Methyl 2-(3-Iodo-4-(naphthalen-1-yl)-8-oxo-1-tosyl-1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3b). 285 mg, 82% yield, white solid, mp: 208−210 °C, Rf = 0.5 (n-hexane:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.9 Hz, 1H), 7.83−7.77 (m, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.49−7.44 (m, 2H), 7.36−7.27 (m, 4H), 7.06−6.97 (m, 2H), 6.56 (s, 1H), 6.27 (dd, J = 10.0, 2.0 Hz, 1H), 6.15 (s, 1H), 5.76 (dd, J = 10.1, 2.0 Hz, 1H), 5.58 (s, 1H), 3.70 (d, J = 5.7 Hz, 3H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.4, 164.3, 147.6, 147.2, 144.1, 143.1, 136.8, 133.4, 131.5, 129.7, 129.4, 129.2, 128.5, 128.5, 128.3, 126.6, 126.0, 125.6, 124.3, 100.7, 75.9, 75.2, 51.8,

21.6; IR (KBr): 3017, 2953, 1720, 1667, 1343, 1163, 1091, 753, 668 cm−1; MS (ESI): m/z 660 (M+Na)+: HRMS (ESI): m/z calcd for C30H25INO5S (M+H)+: 638.0493, found: 638.0473. Methyl 2-(3-Iodo-4-(4-methoxyphenyl)-8-oxo-1-tosyl-1azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3c). 328 mg, 92% yield, yellow semi solid, Rf = 0.4 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 5.4 Hz, 2H), 7.13 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.79 (dd, J = 17.5, 9.1 Hz, 3H), 6.52 (s, 1H), 6.21−6.05 (m, 3H), 5.52 (s, 1H), 3.77 (s, 3H), 3.65 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.6, 164.5, 159.9, 194.4, 147.9, 147.8, 144.0, 143.6, 136.8, 132.9, 130.6, 129.8, 129.4, 129.8, 128.2, 124.7, 113.5, 97.9, 74.4, 74.1, 55.1, 51.8, 21.6; IR (KBr): 3015, 2951, 2843, 1727, 1665, 1343, 1247, 1161, 750, 664 cm−1; MS (ESI): m/z 640 (M+Na)+; HRMS (ESI): m/z calcd for C27H24INO6SNa (M+Na)+: 640.0261, found: 640.0259. Methyl 2-(3-Iodo-8-oxo-4-(p-tolyl)-1-tosyl-1-azaspiro[4.5]deca3,6,9-trien-2-yl)acrylate (3d). 320 mg, 88% yield, pale yellow solid, mp: 156−158 °C, Rf = 0.5 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H), 7.29−7.24 (m, 2H), 7.14 (dd, J = 10.0, 2.6 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.2 Hz, 1H), 6.53 (s, 1H), 6.17 (dd, J = 10.0, 1.8 Hz, 1H), 6.13−6.06 (m, 2H), 5.52 (s, 1H), 3.65 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 184.6, 164.5, 147.8, 147.6, 144.0, 144.0, 139.0, 136.9, 132.9, 129.7,129.6, 129.4, 129.2, 129.1, 128.8, 128.2, 97.6, 74.4, 74.3, 51.8, 21.6, 21.3; IR (KBr): 3022, 2952, 1724, 1665, 1445, 1156, 1034, 748, 664 cm−1; MS (ESI): m/z 624 (M+Na)+; HRMS (ESI): m/z calcd for C27H25INO5S (M+H)+: 602.0493, found: 602.0480. Methyl 2-(4-(3,5-Dimethylphenyl)-3-iodo-8-oxo-1-tosyl-1azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3e). 332 mg, 93% yield, white solid, mp: 149−151 °C, Rf = 0.5 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 2H), 7.29−7.23 (m, 2H), 7.14 (dd, J = 10.0, 2.5 Hz, 1H), 6.91 (s, 1H), 6.78 (dd, J = 15.3, 5.9 Hz, 1H), 6.55 (d, J = 19.6 Hz, 3H), 6.19−6.06 (m, 3H), 5.52 (s, 1H), 3.66 (s, 3H), 2.43 (s, 3H), 2.23 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 184.7, 164.5, 147.8, 147.6, 144.2, 144.0, 137.4, 137.1, 136.9, 132.7, 132.4, 130.8 129.7, 129.4, 129.0, 128.2, 126.9, 97.3, 74.4, 74.1, 51.8, 21.5, 21.2; IR (KBr): 3017, 2922, 2857, 1720, 1667, 1445, 1344, 1160, 1091, 754, 667 cm−1; MS (ESI): m/z 638 (M+Na)+; HRMS (ESI): m/z calcd for C28H26INO5SNa (M+Na)+: 638.0469, found: 638.0475. Methyl 2-(4-(4-Chlorophenyl)-3-iodo-8-oxo-1-tosyl-1azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3f). 248 mg, 70% yield, yellow solid, mp: 194−196 °C, Rf = 0.4 (n-hexane:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.29−7.27 (m, 2H), 7.26−7.23 (m, 2H), 7.14 (dd, J = 10.0, 3.0 Hz, 1H), 6.99−6.92 (m, 2H), 6.84 (dd, J = 10.0, 2.7 Hz, 1H), 6.52 (s, 1H), 6.19 (dd, J = 10.0, 2.0 Hz, 1H), 6.12 (dd, J = 10.1, 2.0 Hz, 1H), 6.09 (s, 1H), 5.50 (s, 1H), 3.63 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.4, 164.3, 147.4, 147.4, 144.1, 142.8, 136.8, 135.3, 133.2, 131.0, 130.8, 130.0, 129.4, 129.1, 128.5, 128.2, 98.4, 74.6, 74.4, 51.7, 21.6; IR (KBr): 2924, 2855, 1719, 1666, 1445, 1343, 1160, 1087, 753, 667 cm−1; MS (ESI): m/z 644 (M+Na)+; HRMS (ESI): m/z calcd for C26H21ClINO5SNa (M+Na)+: 643.9766, found: 643.9770. Methyl 2-(4-(4-Acetylphenyl)-3-iodo-8-oxo-1-tosyl-1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3g). 238 mg, 68% yield, pale yellow liquid, Rf = 0.3 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.29−7.27 (m, 2H), 7.20−7.10 (m, 3H), 6.88 (dd, J = 9.9, 2.4 Hz, 1H), 6.53 (s, 1H), 6.19 (dd, J = 10.0, 1.9 Hz, 1H), 6.14−6.09 (m, 2H), 5.52 (s, 1H), 3.64 (s, 3H), 2.57 (s, 3H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 197.3, 184.3, 164.3, 147.4, 147.2, 144.2, 143.0, 137.4, 137.3, 136.8, 133.4, 130.0, 129.8, 129.4, 129.1, 128.2, 128.0, 98.3, 74.8, 74.5, 51.8, 26.6, 21.6; IR (KBr): 2985, 1737, 1685, 1361, 1249, 1149, 1077, 952, 843, 751, 639 cm−1; MS (ESI): m/z 652 (M+Na)+; HRMS (ESI): m/z calcd for C28H24INO6SNa (M+Na)+: 652.0261 found: 652.0243. Methyl 2-(4-(4-Cyanophenyl)-3-iodo-8-oxo-1-tosyl-1azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3h). 232 mg, 65% yield, yellow solid, mp: 194−196 °C, Rf = 0.4 (n-hexane:EtOAc = 7:3); 1H NMR (300 MHz, CDCl3) δ 7.61 (dd, J = 13.9, 8.2 Hz, 4H), 7.28 (d, J 6936

DOI: 10.1021/acs.joc.7b01285 J. Org. Chem. 2017, 82, 6932−6939

Article

The Journal of Organic Chemistry = 6.4 Hz, 2H), 7.17 (dd, J = 9.8, 5.6 Hz, 3H), 6.89 (dd, J = 10.0, 2.7 Hz, 1H), 6.53 (s, 1H), 6.25−6.07 (m, 3H), 5.50 (s, 1H), 3.62 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.1, 164.2, 147.2, 146.9, 144.2, 142.2, 137.5, 136.7, 136.0, 133.7, 132.0, 130.4, 130.1, 129.5, 129.2, 128.2, 118.1, 113.2, 99.0, 75.4, 74.4, 51.8, 21.6; IR (KBr): 3018, 2953, 2231, 1720, 1668, 1344, 1163, 1090, 849, 757, 668 cm−1; MS (ESI): m/z 635 (M+Na)+; HRMS (ESI): m/z calcd for C27H21I N2O5SNa (M+Na)+: 635.0108 found: 635.0127. Methyl 2-(3-Iodo-8-oxo-1-tosyl-4-(3-(trifluoromethyl)phenyl)-1azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3i). 238 mg, 70% yield, pale yellow solid, mp:168−170 °C, Rf = 0.3 (n-hexane:EtOAc = 7:3); 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.31−7.25 (m, 3H), 7.24−7.16 (m, 2H), 6.88 (dd, J = 10.0, 2.8 Hz, 1H), 6.53 (s, 1H), 6.22−6.08 (m, 3H), 5.52 (s, 1H), 3.64 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.2, 164.3, 147.3, 147.2, 144.2, 142.5, 136.8, 136.4, 133.5, 132.8, 130.8, 130.4, 130.1, 129.4, 129.2, 128.7, 128.2, 126.4, 126.4, 125.9, 125.9, 124.9, 122.2, 99.0, 74.7, 74.4, 51.8, 21.5; IR (KBr): 2924, 2855, 1721, 1669, 1335, 1164, 1089, 755, 668 cm−1; MS (ESI): m/z 678 (M+Na)+; HRMS (ESI): m/z calcd for C27H22 F3INO5S (M+H)+: 656.0210 found: 656.0206. Methyl 2-(3-Iodo-8-oxo-4-(thiophen-2-yl)-1-tosyl-1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3j). 287 mg, 78% yield, white solid; mp: 182−184 °C, Rf = 0.4 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 2H), 7.25−7.19 (m, 3H), 7.03 (dd, J = 10.1, 2.7 Hz, 1H), 6.95 (dd, J = 3.6, 1.2 Hz, 1H), 6.89 (dd, J = 5.1, 3.6 Hz, 1H), 6.70 (d, J = 7.1 Hz, 1H), 6.47 (s, 1H), 6.18 (ddd, J = 21.2, 10.0, 2.0 Hz, 2H), 6.01 (s, 1H), 5.47 (s, 1H), 3.59 (s, 3H), 2.36 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 184.7, 164.5, 147.5, 147.3, 147.3, 144.1, 137.2, 136.7, 132.9, 132.2, 130.5, 129.6, 129.4, 128.3, 127.7, 126.8, 99.6, 74.4, 73.7, 51.8, 21.6; IR (KBr): 2924, 2855,, 1720, 1669, 1344, 1160, 1088, 753, 666 cm−1; MS (ESI): m/z 616 (M+Na)+; HRMS (ESI): m/z calcd for C24 H20 INO5S2Na (M +Na)+: 615.9720, found: 615.9724. tert-Butyl3-(3-iodo-2-(3-methoxy-3-oxoprop-1-en-2-yl)-8-oxo-1tosyl-1-azaspiro[4.5]deca-3,6,9-trien-4-yl)-1H-indole-1-carboxylate (3k). 226 mg, 71% yield, reddish brown solid, mp: 104−106 °C, Rf = 0.2 (n-hexane:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.40−7.29 (m, 1H), 7.26 (s, 1H), 7.25−7.22 (m, 1H), 7.22−7.17 (m, 3H), 7.15−7.07 (m, 2H), 6.89−6.76 (m, 1H), 6.47 (s, 1H), 6.15−5.94 (m, 2H), 5.49 (s, 1H), 3.58 (s, 3H), 2.36 (s, 3H), 1.58 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 184.7, 164.3, 149.1, 147.5, 147.3, 144.1, 136.9, 134.6, 133.2, 129.4, 128.5, 128.2, 124.8, 122.8, 120.5, 115.3, 112.0, 100.3, 84.5, 75.2, 51.8, 28.1, 21.6; IR (KBr): 2985, 1727, 1667, 1363, 1363, 1155, 753, 668 cm−1; MS (ESI): m/z 749 (M+Na)+; HRMS (ESI): m/z calcd for C33H31IN2O7SNa (M+Na)+: 749.0789, found: 749.0770. Methyl 3-(N-(4-Methoxyphenyl)-4-methylphenylsulfonamido)-2methyleneoct-4-ynoate (I-3l). 200 mg, 64%, pale yellow solid, mp: 85−87 °C 1H NMR (300 MHz, CDCl3) δ 7.59 (t, J = 12.5 Hz, 2H), 7.23 (t, J = 10.7 Hz, 2H), 6.90 (t, J = 13.7 Hz, 2H), 6.71 (d, J = 8.9 Hz, 2H), 6.34 (s, 1H), 6.14 (s, 1H), 5.70 (s, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 2.41 (s, 3H), 2.11 (td, J = 7.0, 2.0 Hz, 2H), 1.52−1.37 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6, 159.5, 143.0, 137.0, 132.6, 130.4, 128.8, 128.4, 128.2, 113.6, 89.0, 75.6, 55.2, 52.2, 51.8, 21.7, 21.5, 20.6, 13.5. IR (KBr): 2961, 2230, 1727, 1507, 1350, 1163, 1033, 750 cm-1; MS (ESI): m/z 464 (M+Na)+; HRMS (ESI): m/z calcd for C24H28NO5S (M+H)+: 442.1688 found: 442.1689. General Procedure for the Preparation of 3m−3q. To a solution of 1a/1d (1 mmol) and N-(4-methoxyphenyl)methanesulfonamide (2b−f) (1.1 mmol) in 5 mL of CH2Cl2 was added DABCO (5.60 mg, 0.05 mmol) at 0 °C and stirred up to 30 min. Then, ICl (162.3 mg, 1 mmol) was added dropwise to the reaction mixture at 0 °C. After the completion of reaction (monitored by TLC), saturated aqueous Na2S2O3·5H2O solution (10 mL) was added to the reaction mixture and extracted with CH2Cl2 (2 × 10 mL), washed with brine (2 × 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue obtained was

purified by column chromatography on silica gel (EtOAc:hexanes) to afford 3m−q. Methyl 2-(3-Iodo-1-(methylsulfonyl)-8-oxo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3m). 271 mg, 84% yield, yellow solid, mp: 194−196 °C, Rf = 0.6 (n-hexane:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3) δ 7.30−7.20 (m, 4H), 6.99 (dt, J = 3.8, 2.2 Hz, 2H), 6.89 (dd, J = 10.0, 3.0 Hz, 1H), 6.60 (s, 1H), 6.11 (ddd, J = 12.0, 10.0, 2.6 Hz, 3H), 5.49 (s, 1H), 3.79 (s, 3H), 2.81 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.3, 164.9, 148.1, 145.7, 144.4, 135.8, 135.0, 132.5, 130.9, 129.3, 129.2, 128.7, 128.2, 96.5, 75.0, 73.9, 52.2, 42.6; IR (KBr): 3022, 2952, 1720, 1666, 1340, 1155, 1083, 857, 753, 704 cm−1; MS (ESI): m/z 534 (M+Na)+; HRMS (ESI): m/z calcd for C20H18INO5SNa (M+Na)+: 533.9843 found: 533.9877. Methyl 2-(1-(Ethylsulfonyl)-3-iodo-8-oxo-4-phenyl-1azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3n). 292 mg, 88% yield, pale yellow semi solid, Rf = 0.6 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.35−7.24 (m, 4H), 7.11−7.03 (m, 2H), 7.03− 6.98 (m, 1H), 6.63 (s, 1H), 6.18−6.12 (m, 3H), 5.58 (s, 1H), 3.85 (s, 3H), 3.08−2.84 (m, 2H), 1.30 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 184.4, 164.8, 148.2, 146.3, 144.2, 136.2, 136.6, 132.6, 130.5, 129.4, 129.1, 128.4, 128.1, 96.7, 75.0, 74.1, 52.2, 49.6, 7.9; IR (KBr): 2994, 2253, 1720, 1665, 1336, 1148, 1045, 912, 856, 780, 727, 643 cm−1; MS (ESI): m/z 548 (M+Na)+; HRMS (ESI): m/z calcd for C21H20NO5SINa (M+Na)+: 548.0006 found: 548.0005. Methyl 2-(1-(Cyclopropylsulfonyl)-3-iodo-8-oxo-4-phenyl-1azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3o). 292 mg, 86% yield, pale yellow semi solid, Rf = 0.4 (n-hexane:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3) δ 7.37−7.27 (m, 4H), 7.06 (dt, J = 3.9, 2.3 Hz, 2H), 7.02−6.97 (m, 1H), 6.64 (s, 1H), 6.15 (d, J = 9.9 Hz, 3H), 5.58 (s, 1H), 3.85 (s, 3H), 2.39−2.30 (m, 1H), 1.20−1.10 (m, 2H), 0.98− 0.90 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 184.5, 164.8, 148.3, 147.3, 144.2, 137.1, 134.0, 132.7, 130.1, 129.4, 129.1, 128.6, 128.1, 97.1, 74.8, 74.1, 52.1, 32.3, 6.6, 6.4; IR (KBr): 33018, 2358, 1720, 1666, 1340, 1151, 1042, 858, 701 cm−1; MS (ESI): m/z 560 (M+Na)+; HRMS (ESI): m/z calcd for C22H20NO5SINa (M+Na)+: 560.0013 found: 560.0005. Methyl 2-(1-(Benzylsulfonyl)-3-iodo-8-oxo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3p). 282 mg, 76% yield, pale yellow, Semi solid, Rf = 0.4 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.41−7.23 (m, 9H), 7.02 (d, J = 7.3 Hz, 2H), 6.86− 6.75 (m, 1H), 6.66 (s, 1H), 6.13 (s, 1H), 6.08 (d, J = 10.0 Hz, 1H), 5.98 (d, J = 10.0 Hz, 1H), 5.51 (s, 1H), 4.22−4.13 (m, 2H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 184.4, 164.87, 147.8, 146.1, 144.3, 136.2, 134.7, 132.6, 131.0, 130.0, 129.4, 127.1, 129.0, 128.7, 128.6, 128.1, 128.0, 96.4, 75.0, 74.2, 61.0, 52.2; IR (KBr): 3059, 2951, 2253, 1720, 166, 1626, 1345, 1154, 1078, 731, 700, 646 cm−1; MS (ESI): m/z 610 (M+Na) + ; HRMS (ESI): m/z calcd for C26H22NO5SINa (M+Na)+: 610.0169 found: 610.0161. Methyl 2-(1-((2-Bromophenyl)sulfonyl)-3-iodo-8-oxo-4-(p-tolyl)1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (3q). 339 mg, 84% yield, pale yellow, Semi solid; Rf = 0.4 (n-hexane:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 7.8, 1.9 Hz, 1H), 7.70 (dd, J = 7.8, 1.3 Hz, 1H), 7.42−7.28 (m, 3H), 7.06 (d, J = 7.8 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 6.86 (dd, J = 10.1, 3.0 Hz, 1H), 6.38 (s, 1H), 5.99 (dd, J = 10.2, 2.0 Hz, 1H), 5.95 (s, 1H), 5.91 (dd, J = 10.1, 2.0 Hz, 1H), 5.84 (s, 1H), 3.80 (s, 3H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.3, 164.8, 148.0, 146.3, 143.7, 139.1, 137.9, 137.1, 135.5, 134.8, 133.9, 132.2, 129.4, 129.2, 128.8, 127.5, 121.9, 97.7, 74.9, 73.7, 52.0, 21.3; IR (KBr): 2950, 2922, 2252, 1721, 166, 1438, 1334, 1161, 1030, 911, 729, 620 cm−1; MS(ESI): m/z 690 (M+Na)+; HRMS (ESI): m/z calcd for C26H21BrINO5SNa (M+Na)+ 687.9266 found: 687.9267. Methyl 2-(2-Iodo-5,5-dioxido-8-oxo-1-phenyl-6,6a,7,8-tetrahydro-3H-benzo[c]pyrrolo[1,2-b]isothiazol-3-yl)acrylate (4). LHMDS in THF (0.3 mL 1 M solution in THF, 1.5 mmol) was added to a solution of 3m (100 mg, 1 mmol) in THF (5 mL) at −78 °C. The progress of the conversion was monitored by TLC. Upon completion of the reaction, the mixture was warmed to 0 °C, neutralized with aq. saturated NH4Cl (3 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were sequentially washed with aq. saturated NH4Cl 6937

DOI: 10.1021/acs.joc.7b01285 J. Org. Chem. 2017, 82, 6932−6939

Article

The Journal of Organic Chemistry (2 × 10 mL) and brine (2 × 10 mL), dried (Na2SO4), and evaporated. The residue was dried (high vacuum) and chromatographed (5% EtOAc) to give 75 mg of 4. 75 mg, 75% yield, pale yellow solid, mp: 85−87 °C; Rf = 0.5 (nhexane:EtOAc = 4:6); 1H NMR (400 MHz, CDCl3) δ 7.44−7.38 (m, 3H), 7.24−7.18 (m, 2H), 7.08 (dd, J = 10.3, 1.5 Hz, 1H), 6.56 (s, 1H), 6.19−6.06 (m, 2H), 5.66 (s, 1H), 3.84−3.82 (m, 3H), 3.51 (dd, J = 12.0, 5.9 Hz, 1H), 3.37−3.22 (m, 2H), 2.30 (dt, J = 16.5, 3.6 Hz, 1H), 1.97 (dd, J = 17.4, 5.4 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 193.8, 164.8, 146.4, 146.1, 137.2, 133.3, 132.3, 129.5, 129.5, 129.0, 128.6, 95.8, 78.7, 71.1, 53.5, 52.1, 41.1, 36.4; IR (KBr): 2924, 2359, 1722, 1682, 1314, 1149, 1075, 766, 731, 704 cm−1; MS (ESI): m/z 534 (M +Na)+; HRMS (ESI): m/z calcd for C20H19INO5S (M+H)+: 512.0023 found: 512.0011. Methyl 2-(3-(4-Hydroxyphenyl)-1-(methylsulfonyl)-8-oxo-4phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (5). To a solution of 3m (100 mg, 0.195 mmol), K3PO4 (165 mg, 0.78 mmol), Pd(PPh3)4 (10 mol%), and (4- hydroxyphenyl)boronic acid (41 mg, 0.29 mmol) in DMF (5 mL) was degassed with N2 for 20 min. The reaction mixture was heated at 80 °C for 6 h. After the completion of reaction, DMF was removed under vacuum, and the residue was dissolved in EtOAc (5 mL), filtered through Celite, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (EtOAc in n-hexane) to afford 5. 63 mg, 68% yield, yellow semi solid, Rf = 0.3 (n-hexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.45 (dd, J = 10.1, 2.9 Hz, 1H), 7.22−7.14 (m, 3H), 7.00 (dd, J = 7.9, 1.5 Hz, 2H), 6.92 (dd, J = 10.1, 2.9 Hz, 1H), 6.87−6.82 (m, 2H), 6.58−6.52 (m, 2H), 6.40 (s, 1H), 6.33 (dd, J = 10.1, 2.0 Hz, 1H), 6.13−5.99 (m, 3H), 5.79 (s, 1H), 3.73 (s, 3H), 2.93 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 185.0, 165.7, 155.9, 149.8, 147.7, 133.7, 132.5, 131.8, 130.5, 130.2, 130.1, 128.4, 128.3, 128.1, 124.1, 115.2, 74.0, 69.6, 52.1, 42.4; IR (KBr): 3414, 3022, 2953, 1720, 1665, 1516, 1441, 1338, 1154, 956, 796, 753, 699 cm−1; MS (ESI): m/z 500 (M+Na)+; HRMS (ESI): m/z calcd for C26H23NO6S (M+Na)+: 500.1138 found: 500.1113. (E)-Methyl-2-(3-(3-methoxy-3-oxoprop-1-en-1-yl)-1-(methylsulfonyl)-8-oxo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-yl) Acrylate (6). To a solution of 3m (100 mg, 0.196 mmol), Pd(OAc)2 (5 mg, 0.196 mmol, 10 mol%), Bu4NBr (63 mg, 0.196 mmol), NaHCO3 (41 mg, 0.49 mmol), and methyl acrylate (19 mg, 0.216 mmol) in DMF (5 mL). The reaction mixture was heated at 80 °C for 5 h. After the completion, reaction was quenched by aqueous NH4Cl (10 mL). The mixture was extracted with EtOAc (2 × 5 mL) organic layer was washed with H2O (5 mL) followed by brine (5 mL), dried over Na2SO4, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (EtOAc in n-hexane) to afford 6. 67.5 mg, 74% yield, yellow solid, mp: 98−100 °C, Rf = 0.5 (nhexane:EtOAc = 7:3); 1H NMR (500 MHz, CDCl3) δ 7.38−7.25 (m, 5H), 7.10−7.06 (m, 2H), 7.03−6.99 (m, 1H), 6.90 (dd, J = 10.0, 3.0 Hz, 1H), 6.62 (s, 1H), 6.29−6.22 (m, 2H), 6.15 (dd, J = 10.0, 1.8 Hz, 1H), 5.87 (dd, J = 9.1, 7.2 Hz, 2H), 3.83 (s, 3H), 3.67 (s, 3H), 2.90 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.2, 166.4, 165.3, 148.5, 145.6, 145.3, 135.0, 131.2, 129.7, 129.5, 128.9, 128.2, 122.1, 73.4, 67.8, 52.3, 51.8, 42.8; IR (KBr): 3021, 2952, 1716, 1667, 1438, 1342, 1155, 969, 755, 700 cm−1; MS (ESI): m/z 492 (M+Na)+; HRMS (ESI): m/z calcd for C24H24NO7S (M+H)+: 470.1268 found: 470.1298. Methyl 2-(4-(4-Methoxyphenyl)-8-oxo-3-(phenylethynyl)-1-tosyl1-azaspiro[4.5]deca-3,6,9-trien-2-yl)acrylate (7). To a solution of 3c (100 mg, 0.25 mmol) in triethylamine (3 mL) was added to a mixture of Pd(PPh3)2Cl2 (11 mg, 0.025 mmol, 10 mol%) and copper(I) iodide (10 mg, 0.05 mmol, 20 mol%) in a flame-dried flask. The mixture was degassed with N2 for 15 min. Phenylacetylene (18 mg, 1.78 mmol) was added, and the mixture was stirred at room temperature overnight. After the completion of reaction, the mixture was diluted with water (3 mL) and then the mixture was extracted with EtOAc (10 mL × 2). The combined organic layers were dried with anhydrous Na2SO4, filtered through Celite, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (EtOAc in n-hexane) to afford 7.

84 mg, 88% yield, pale yellow semi solid, Rf = 0.3 (n-hexane:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.25 (dtt, J = 8.0, 3.0, 1.9 Hz, 11H), 6.81−6.74 (m, 3H), 6.49 (s, 1H), 6.25 (dt, J = 10.2, 1.9 Hz, 2H), 6.09 (s, 1H), 5.61 (s, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.43 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 184.9, 165.0, 160.1, 148.8, 148.1, 144.0, 141.8, 138.2, 136.9, 131.6, 130.2, 130.1, 129.8, 129.6, 129.4, 128.9, 128.3, 122.0, 121.9, 113.5, 97.1, 82.2, 73.2, 69.2, 55.2, 51.7, 21.5; IR (KBr): 2952, 2839, 2204, 1722, 1667, 1605, 1510, 1337, 1249, 1160, 1067, 909, 729, 667 cm−1; MS (ESI): m/z 614 (M+Na)+; HRMS (ESI): m/z calcd for C35H29NO6SNa (M+Na)+: 614.1608 found: 614.1628.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01285. X-ray crystallographic analysis of 4 (CIF) Copies of 1H and 13C NMR spectra of all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Chada Raji Reddy: 0000-0003-1491-7381 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Council of Scientific and Industrial Research (CSIR)New Delhi for research fellowship to R.R. and K.W. and for financial support to C.R.R. and S.K.P. as part of XII five-year programme project under ORIGIN (CSC-108). Authors thank Dr. B. Sridhar for his support in X-ray crystallography analysis.

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DOI: 10.1021/acs.joc.7b01285 J. Org. Chem. 2017, 82, 6932−6939